ITR: Collaborative Research: (ASE+NHS+EVS)-(sim+dmc+int): In Silico De Novo Protein Design: A Dynamically Data Driven, (DDDAS), Computational and Experimental Framework

ITR：协作研究：(ASE NHS EVS)-(sim dmc int)：计算机从头蛋白质设计：动态数据驱动、(DDDAS)、计算和实验框架

• 批准号: 0427103
• 负责人: Dimitrios Morikis
• 金额: --
• 依托单位: University of California-Riverside
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-15 至 2007-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0427103&HistoricalAwards=false
• 关键词: ITR; Collaborative; Research; ASE+NHS+EVS; sim+dmc+int

ABSTRACTPI: Dimitrios Morikis Institution: University of California RiversideProposal Number: 0427103Research: A challenge in computational protein design is the discovery of novel proteins, which are compatible with either target template structures or arbitrarily three dimensional structures. This research is a dynamically data driven application systems, (DDDAS), effort through an integrative research framework, (i.e., computational, physicochemical, and biochemical approaches) for the in silico de novo design of peptides and proteins. The primary aims of the project are (i) in silico sequence selection and folding specificity calculations through a novel computational framework that is based on mixed-integer optimization and deterministic global optimization, (ii) in vitro and in silico characterization via NMR, structure determination, and molecular dynamics, (iii) protein expression, structural characterization and activity measurements of predicted sequences, and (iv) the development of a web-based WorkBench support system for de novo peptide/protein design which will be freely available to all researchers. The biological systems for testing and validating the proposed framework include the C3a anaphylatoxin (aims (i)-(iv)), and human beta defensins (aims (i), molecular dynamics of (ii) and (iv)). Intellectual Merit:The planned effort involves an interdisciplinary team (Floudas, Lambris, Morikis) from three institutions (Princeton, U. Penn, U. California at Riverside). Their expertise spans the fields of complement biology, protein chemistry, structural biology, mathematical modeling and analysis, combinatorial and global optimization, scientific computing, and bioengineering, and the project is an integrative computational and experimental effort. These developments can expedite significantly the drug discovery process, address important tasks in the design of new drugs, and the proposed novel concept of a web-based WorkBench will be the first such service to the scientific community. Broader Impacts: Using IT and DDDAS techniques, in a uniquely symbiotic computational and experimental framework, this project will lay the groundwork for making significant advances in the discovery of new drugs. This framework for in silico prediction of new sequences which fold selectively to structural templates and their experimental validation will allow rapid screening of novel alternatives and will lead into better and faster drug discovery which has direct impact in our society. The proposed effort integrates participation of graduate students, postdoctoral students, and undergraduate students into the research, thereby providing multidisciplinary training opportunities. The co-PIs have records in research with undergraduate students as part of their junior independent work, as well as senior thesis work. All three institutions have policies for attracting students and employees from traditionally under-represented groups. The co-PIs are committed to working with these students and will work pro-actively to attract them to this research project, the seminar series, the journal club, and the graduate level course. The co-PIs have strong records of educating undergraduate and graduate students, and post-doctoral associates from under-represented groups. The results of the research will be disseminated to the entire scientific community through publications in archival journals, refereed proceedings, and via presentations at conferences. Furthermore, the development of the web-based WorkBench for the de novo design of peptide/proteins will provide, for the first time, service to the scientific community.

摘要/ abstract摘要：Dimitrios Morikis机构：California University of riverside项目编号：0427103研究：计算蛋白质设计的一个挑战是发现与靶模板结构或任意三维结构兼容的新型蛋白质。本研究是动态数据驱动应用系统（DDDAS），通过综合研究框架（即计算，物理化学和生化方法）为肽和蛋白质的从头开始设计而努力。该项目的主要目标是(i)通过基于混合整数优化和确定性全局优化的新型计算框架进行硅序列选择和折叠特异性计算；（ii）通过核磁共振、结构测定和分子动力学进行体外和硅表征；（iii）预测序列的蛋白质表达、结构表征和活性测量。（iv）开发一个基于网络的工作台支持系统，用于从头设计肽/蛋白质，该系统将免费提供给所有研究人员。用于测试和验证拟议框架的生物系统包括C3a过敏毒素(aims （i)-(iv)）和人类β防御素(aims （i), （ii）和（iv）的分子动力学）。智力价值：计划中的努力包括来自三个机构（普林斯顿大学、宾夕法尼亚大学、加州大学河滨分校）的跨学科团队（florida, Lambris, Morikis）。他们的专业知识涵盖补体生物学、蛋白质化学、结构生物学、数学建模和分析、组合和全局优化、科学计算和生物工程等领域，该项目是一个综合计算和实验的项目。这些发展可以大大加快药物发现过程，解决新药设计中的重要任务，并且提出的基于网络的工作台的新概念将是科学界的第一个此类服务。更广泛的影响：在独特的共生计算和实验框架中，使用IT和DDDAS技术，该项目将为在新药发现方面取得重大进展奠定基础。该框架用于对选择性折叠成结构模板的新序列的计算机预测及其实验验证，将允许快速筛选新的替代品，并将导致更好，更快的药物发现，这对我们的社会有直接影响。提议的努力将研究生、博士后和本科生的参与纳入研究，从而提供多学科的培训机会。作为本科学生初级独立工作的一部分，以及高级论文工作的一部分，共同pi都有研究记录。这三所大学都有吸引传统上代表性不足群体的学生和员工的政策。合作项目负责人致力于与这些学生合作，并将积极地吸引他们参加本研究项目、系列研讨会、期刊俱乐部和研究生课程。在培养来自弱势群体的本科生、研究生和博士后助理方面，合作pi有着良好的记录。这项研究的结果将通过在档案期刊上的出版物、经过评审的论文和在会议上的报告向整个科学界传播。此外，基于web的肽/蛋白质从头设计工作台的开发将首次为科学界提供服务。